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      Remdesivir versus ritonavir/lopinavir in COVID-19 patients

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      Irish Journal of Medical Science
      Springer London

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          Abstract

          To the Editor: The new coronavirus SARS-CoV-2 is responsible for the current global pandemic COVID-19. To date, data indicate 1.11 million deaths. [1] Several vaccines and monoclonal antibodies to SARS-CoV-2 are in clinical trials. In the meantime, several studies have been conducted to test the risk factors COVID-19 and drugs with antiviral efficacy against SARS-CoV-2. [2] The trials have attributed some efficacy to the antivirals Remdesivir and Ritonavir/lopinavir. However, recent literature evidence shows some differences between the two antiviral treatments. Remdesivir is a drug of the nucleotide analogues family, with antiviral activity against several RNA viruses, and is considered a potential antiviral agent against SARS-CoV-2. Lopinavir is an inhibitor of HIV-1 protease, which is in combination with ritonavir to increase its plasma half-life time. Lopinavir is associated with an in vitro inhibitory activity against SARS-CoV and SARS-CoV-2. [3] In these months, several epidemiological studies have been carried out to evaluate the antiviral efficacy of the above mentioned drugs. Recent evidence associates Remdesivir’s significant clinical improvements in COVID-19 positive patients hospitalized, leading to a reduction in mortality and a decrease in recovery time. [4] Recent evidence suggests that Ritonavir/lopinavir is not an effective treatment for severe and hospitalized COVID-19 patients, excluding any benefit on the probability of mortality from COVID-19 and length of hospital stay, highlighting discrepancies between reported in vitro and in vivo results. Probably further studies are necessary to understand the most effective dose, also considering the safety profile of the drug, in the treatment of COVID-19 viral infection. However, the existing EBM shows that today the drug with the most effective antiviral SARS-CoV-2 and improving clinical parameters is Remdesivir. However, we believe that further epidemiological studies are needed to clarify the optimal dose to be used in severe COVID-19 patients, and possible dose modifications to be made to avoid drug-drug interaction, and drug-pathology, considering that the COVID-19 patient is a complex patient. [5] Epidemiological studies associate Remdesivir with the gold standard of SARS-CoV-2 antiviral therapy, demonstrating some efficacy, and with Ritonavir/lopinavir association, there are no results of SARS-CoV-2 antiviral efficacy. However, further studies are needed to provide further data on these COVID-19 treatments.

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          Therapeutic Strategies for SARS-CoV-2 acting on ACE-2

          Dear Editor, Considering the mechanisms of intracellular penetration of SARS-CoV-2, the significant related risk factors, changes in ACE-2 concentration during infection, and the complex interaction of the RAS system with COVID-19, [1,2] modulation of RAS at certain stages of infection could be considered an important therapeutic strategy. In particular, observational clinical studies indicate that in most cases respiratory problems occur a few days after contracting SRAS-CoV-2 infection, suggesting that this may not be caused by direct viral damage, but suggesting that other mechanisms may be responsible, such as loss of ACE2 function and dysregulation of the RAS system pathways resulting in non-activation of the Ace-2/Ang [1], [2], [3], [4], [5], [6], [7]/Mas receptor axis [3,4] and hyperactivation of the axis Ace/Ang-2/ AT1r. Probably the binding of the peak coronavirus protein leads to exhaustion of ACE2 receptors, which in turn causes the loss of the protective pulmonary function of the ACE2/MAS axis. [5,6] In addition to the loss of protective function of the ACE2/MAS pathway, the resulting hyperactivation of the ACE/AngII/AT1r pathway leads to excessive tissue Ang II production and stimulation of AT1r with vasoconstriction, inflammatory and fibrotic effects contributing to the epithelial lesion of lung tissue. The presence and formation of pulmonary fibrotic tissue in particular can cause serious damage in the pulmonary architecture with consequent physiological dysfunction. [7] The ACE-2 activation pathway on the contrary leads to synthesis of Ang [1], [2], [3], [4], [5], [6], [7] and Ang [1], [2], [3], [4], [5], [6], [7], [8], [9] with stimulation of AT2r receptors with antifibrotic, antiflammatory and vasodilating effects. [8] Based on this, we believe that in the early stages of viral infection, a decrease or blockage of ACE-2 could reduce the intracellular viral penetration, in the most severe stages of infection where lung dysfunction begins to occur, an increase of ACE-2 for example with soluble ACE-2 (rhACE2) or with RAS acting agents can protect against lung injury. While current evidence does not recommend discontinuation of treatments with RAS modifying agents, we believe that modifications of RAS and ACE-2 at the right time could be important to combat COVID-19 infection. Epidemiological studies are necessary to generate the necessary evidence. [9,10]
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            Correlation between renin-angiotensin system and Severe Acute Respiratory Syndrome Coronavirus 2 infection: What do we know?

            The first cases of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2 or COVID-19) infections were recorded in China in November 2019. Since its appearance in China at the end of last year, the virus has spread to all continents causing a “global pandemic”. To date, some aspects remain to be investigate about the pathophysiology of this viral infection. One of the aspects to be still clarified is the correlation between the renin-angiotensin system (RAS) and SARS-CoV-2 infection. RAS is a physiological system playing a key role in different human body functions regulation. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE-2), a component of RAS, as a potential factor of cell penetration and infectivity; in addition, in the different infection stages, a functional variation of the RAS has been noted. In this article, we discuss the correlation between the role of RAS and system-modifying agents, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs) and direct renin inhibitors (DRIs), with SARS-CoV-2 infection.
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              Author and article information

              Contributors
              antonio.vitiello2@uslumbria1.it
              francesco.ferrara@uslumbria1.it
              Journal
              Ir J Med Sci
              Ir J Med Sci
              Irish Journal of Medical Science
              Springer London (London )
              0021-1265
              1863-4362
              18 November 2020
              : 1-2
              Affiliations
              Pharmaceutical Department, Usl Umbria 1, A.Migliorati Street, 06132 Perugia, Italy
              Author information
              https://orcid.org/0000-0003-2623-166X
              https://orcid.org/0000-0001-9298-6783
              Article
              2440
              10.1007/s11845-020-02440-y
              7673242
              33206336
              b8f68cd4-026d-486b-9f7f-55defe6cdb35
              © Royal Academy of Medicine in Ireland 2020

              This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

              History
              : 12 November 2020
              : 13 November 2020
              Categories
              Letter to the Editor

              Medicine
              Medicine

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